Revlimid Combo Fails as Prostate Cancer Therapy

Action Points

This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain that a large phase III placebo-controlled trial failed to show improved outcomes with the addition of lenalidomide to docetaxel plus prednisone in patients with castration-resistant prostate cancer who had not previously received chemotherapy.

Note that adverse events were substantially higher in the lenalidomide arm, resulting in more dose reductions for both lenalidomide and docetaxel and completion of fewer chemotherapy cycles.

VIENNA -- Adding lenalidomide (Revlimid) to the chemotherapy regimen led to greater toxicity and worse survival in patients with untreated castration-resistant prostate cancer (CRPC), results of a large international trial showed.

Men randomized to a regimen of lenalidomide, docetaxel, and prednisone, had a 53% increased mortality hazard, a 32% greater hazard for progression, and significantly higher rates of neutropenia, febrile neutropenia, and multiple non-hematologic adverse events.

Investigators found no outcomes that favored lenalidomide over a docetaxel-prednisone-placebo combination, Daniel Petrylak, MD, of Yale Cancer Center, reported here at the European Society for Medical Oncology meeting.

"Further analysis of the data is underway to help elucidate the observed results in the lenalidomide arm," he said.

Lenalidomide has antiangiogenic and immunomodulatory properties that suggested therapeutic potential in CRPC. In phase I/II clinical trials, lenalidomide demonstrated activity and tolerability when used as a single agent or in combination with docetaxel and prednisone, said Petrylak.

The promising early results provided the basis for a multicenter, randomized phase III clinical trial of lenalidomide in combination with docetaxel and prednisone as first-line therapy for metastatic CRPC.

Investigators randomized patients to lenalidomide 25 mg/d, docetaxel 75 mg/m2 on day 1, and prednisone 5 mg BID, or to placebo and the same two drugs at the same doses. Treatment continued on 21-day cycles until disease progression, and follow-up continued for 5 years after discontinuation of treatment.

The final analysis included 1,059 patients. Treatment groups did not differ significantly with respect to baseline characteristics.

Data analysis showed a median OS of 77 weeks in the lenalidomide arm, whereas the median had yet to be reached in the placebo group (HR 1.53, P=0.0017). Median PFS was 45 weeks with lenalidomide and 46 weeks with placebo (HR 1.32, P=0.0187).

Comparisons of other response outcomes showed no difference between treatment groups:

50% PSA decline: 58.7% with lenalidomide versus 58% with placebo

30% PSA decline: 67.2% versus 67.1%

Complete response: 0.9% versus 1.5%

Partial response: 21.2% versus 22.8%

Stable disease: 53.8% versus 59.7%

Progressive disease: 8.8% versus 5.9%

Overall response rate: 22.1% versus 24.3%

Patients in the lenalidomide group completed fewer therapy cycles (six versus eight), required more dose reductions for lenalidomide and docetaxel, and received a lower average cumulative dose of study drug and docetaxel.

"All dose reductions were due to adverse events, except for two dose reductions of docetaxel due to other reasons," Petrylak said.

The lenalidomide combination came out on the wrong side of adverse event comparisons for:

Neutropenia: 21.7% versus 16.3% for placebo (P=0.027511)

Febrile neutropenia: 11.8% versus 4.6% (P=0.000024)

Diarrhea: 7% versus 2.3% (P=0.000346)

Pulmonary embolism: 6.5% versus 1.5% (P=0.000050)

Dyspnea: 4.2% versus 1.7% (P=0.027146)

Pneumonia: 4.6% versus 1.2% (P=0.001228)

Invited discussant Robert Jones, MD, said the negative results have implications and consequences that go beyond this one clinical trial.

"I think we can entirely conclude that there is no future for this combination in prostate cancer," said Jones, of the University of Glasgow in Scotland. "This had direct consequences for the patients who took part in the experimental arm of this study, whose care was compromised as a result."

"This was also a large study, 1,059 patients, and these patients were lost to other trials of important, more active agents that were in trials taking place at this time, thereby slowing the progress of medical discovery," he said. "I think it is also reasonable to conclude that, whatever the cause for this detrimental effect, that there is probably no future for lenalidomide in prostate cancer in any context."

Acknowledging the benefits of hindsight in evaluating the study, Jones nonetheless cited several reasons to question the wisdom of conducting a large phase III trial involving the combination of lenalidomide to docetaxel.

The dose-limiting toxicity of both drugs is neutropenia. Only weak proof-of-concept data existed for use of lenalidomide in prostate cancer. Similarly, limited data had accumulated regarding the efficacy and safety of lenalidomide in combination with docetaxel, he pointed out.

"I do think that the prior hypothesis for this combination was by no means proven before entering into this trial," Jones said.